Novel Lipophilic Acetohydroxamic Acid Derivatives Based on Conformationally Constrained Spiro Carbocyclic 2,6-Diketopiperazine Scaffolds with Potent Trypanocidal Activity


Fytas, C; Zoidis, G; Tzoutzas, N; Taylor, MC; Fytas, G; Kelly, JM; (2011) Novel Lipophilic Acetohydroxamic Acid Derivatives Based on Conformationally Constrained Spiro Carbocyclic 2,6-Diketopiperazine Scaffolds with Potent Trypanocidal Activity. Journal of medicinal chemistry, 54 (14). pp. 5250-5254. ISSN 0022-2623 DOI: https://doi.org/10.1021/jm200217m

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Abstract

We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC(50) = 6.8 nM) and T. cruzi (IC(50) = 0.21 mu M).

Item Type: Article
Keywords: trypanosoma-brucei, inhibitors, design, protein
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
PubMed ID: 21542562
Web of Science ID: 292892300028
URI: http://researchonline.lshtm.ac.uk/id/eprint/264

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